Oral allopregnanolone for FXTAS to be tested in PureTech’s Phase 2 trial

Company awarded $11.4M DoD grant for trial with UC Davis researchers

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

Share this article:

Share article via email
Clipboard with a checklist of the words

PureTech Health is planning a Phase 2 clinical trial to test its lead therapeutic candidate LYT-300 — an oral formulation of allopregnanolone — in people with fragile X-associated tremor/ataxia syndrome (FXTAS).

The company has been awarded a grant of up to $11.4 million from the U.S. Department of Defense (DoD). The funding will be used to conduct the trial, which will be run in collaboration with the University of California, Davis (UC Davis).

“This award from the DoD allows us to expand our evaluation of LYT-300, a candidate with a wide variety of potential indications, into FXTAS, an area of tremendous need where otherwise normally developed, aging individuals suffer from significant neurodegeneration,” Eric Elenko, PhD, PureTech’s chief innovation officer, said in a company press release.

Recommended Reading
FXTAS | Fragile X News Today | illustration of woman talking to medical professional

Study Supports Development of Preventive Treatments for FXTAS

‘No primary treatments for FXTAS’

“Currently, there are no primary treatments for FXTAS,” said Randi Hagerman, MD, medical director of the UC Davis MIND Institute and chair in fragile X research. She added that the disorder is a “devastating, late-onset neurodegenerative condition characterized by cognitive decline, tremors in the hands and balance problems.”

“I am excited to be working with PureTech to evaluate their oral prodrug of allopregnanolone (LYT-300), and I am optimistic that this award will help accelerate the development of this potential first therapy for FXTAS,” said Hagerman, who will serve as a co-principal investigator on the upcoming trial.

FXTAS is a condition that, like fragile X syndrome, is caused by mutations in the FMR1 gene. Whereas symptoms of fragile X are apparent from childhood, FXTAS is characterized by symptoms that develop in the latter decades of life in people who have otherwise had normal development.

FXTAS often mistaken for other neurological disorders

Symptoms of FXTAS commonly include tremor, ataxia (coordination problems), and cognitive decline. The condition, which was first formally described by Hagerman and colleagues in the early 2000s, is often mistaken for other neurological disorders like Alzheimer’s or Parkinson’s disease.

Allopregnanolone is a molecule naturally made in the brain that can increase the release of GABA, a major brain signaling molecule, by binding to GABAA receptor proteins at the surface of nerve cells.

Given that problems in GABA signaling have been linked to anxiety, depression, and cognitive deficits, allopregnanolone is thought to have potential therapeutic benefits in FXTAS and other neurological and neuropsychiatric indications.

Data from a Hagerman-sponsored Phase 2 trial (NCT02603926) involving six men with FXTAS suggested that allopregnanolone, administered directly into the bloodstream (infusion) once weekly for three months, could improve patients’ cognitive function.

However, given that this route of administration is burdensome for patients, especially with long-term use, PureTech created an oral formulation of allopregnanolone, LYT-300.

Recommended Reading
protein levels and FXTAS

Key Proteins Less Abundant in Brain Tissue of Late-stage FXTAS Patients

LYT-300 contains prodrug that’s converted to allopregnanolone in the body

LYT-300 was developed using the company’s Glyph technology platform, which leverages the body’s natural absorption and transport processes of fatty molecules to allow the oral administration of therapies that otherwise could not be taken orally.

PureTech’s lead experimental therapy contains an allopregnanolone prodrug, or an inactive molecule that’s converted into allopregnanolone once it’s in the body.

In a Phase 1 trial (NCT05129865), LYT-300 was shown to be generally safe and well-tolerated in healthy volunteers. Data also showed successful GABAA receptor target engagement.

The future Phase 2 trial will evaluate LYT-300’s safety, tolerability, and efficacy against a placebo in FXTAS patients. No further details are provided at this time.

“We look forward to collaborating with Dr. Randi Hagerman and her team at UC Davis to bring the potential of allopregnanolone to the thousands of individuals with FXTAS in need of a treatment,” Elenko said.

LYT-300 is also being evaluated as a potential treatment for anxiety disorders and postpartum depression, with Phase 2 trials currently ongoing or in the pipeline.